Identification of Dynamin-2-Mediated Endocytosis as a New Target of Osteoporosis Drugs, Bisphosphonates

Masaike, Yuka; Takagi, Toshihisa; Hirota, Masataka; Yamada, Joe; Ishihara, Satoru; Yung, Tetsu M.C.; Inoue, Takamitsu; Sawa, Chika; Sagara, Hiroshi; Sakamoto, Satoshi; Kabe, Yoshio; Takahashi, Yasuyuki; Yamaguchi, Yuki; Handa, Hiroshi

doi:10.1124/mol.109.059006

Cited by 23 publications

(17 citation statements)

References 39 publications

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“…Cleaved Notch3 is a key determinant of Notch3 biology, and DNM-mediated endocytosis is required for Jagged1-mediated Notch3 activation. Targeting Notch3 pathway activation with DNM inhibitors (20) combined with paclitaxel could be considered for future clinical investigation.…”

Section: Discussionmentioning

confidence: 99%

Notch3 Pathway Alterations in Ovarian Cancer

Liu

Ivan

et al. 2014

Cancer Research

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Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited OvCa growth and induced apoptosis. Importantly, we found that DNM-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.

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Section: Discussionmentioning

confidence: 99%

Notch3 Pathway Alterations in Ovarian Cancer

Liu

Ivan

et al. 2014

Cancer Research

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“…Of clinical interest, mutations in dynamin’s PH domain are associated with dominant intermediate Charcot-Marie-Tooth disease (Zuchner et al, 2005). Moreover, it has been demonstrated that alendronate, a nitrogen-containing bisphosphonate commonly used to treat bone loss associated with osteoporosis, binds dynamin’s PH domain and inhibits dynamin’s catalytic activity (Masaike et al, 2010). These reports further support the idea that the interaction of the dynamin PH domain with Pyk2 potentially inhibits the GTPase activity of dynamin.…”

Section: Discussionmentioning

confidence: 99%

Dynamin and PTP-PEST cooperatively regulate Pyk2 dephosphorylation in osteoclasts

Eleniste

Shivanna

et al. 2012

The International Journal of Biochemistry & Cell Biology

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Bone loss is caused by the dysregulated activity of osteoclasts which degrade the extracellular bone matrix. The tyrosine kinase Pyk2 is highly expressed in osteoclasts, and mice lacking Pyk2 exhibit an increase in bone mass, in part due to impairment of osteoclast function. Pyk2 is activated by phosphorylation at Y402 following integrin activation, but the mechanisms leading to Pyk2 dephosphorylation are poorly understood. In the current study, we examined the mechanism of action of the dynamin GTPase on Pyk2 dephosphorylation. Our studies reveal a novel mechanism for the interaction of Pyk2 with dynamin, which involves the binding of Pyk2’s FERM domain with dynamin’s plextrin homology domain. In addition, we demonstrate that the dephosphorylation of Pyk2 requires dynamin’s GTPase activity and is mediated by the tyrosine phosphatase PTP-PEST. The dephosphorylation of Pyk2 by dynamin and PTP-PEST may be critical for terminating outside-in integrin signaling, and for stabilizing cytoskeletal reorganization during osteoclast bone resorption.

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“…The AX-ALN solution prepared in our laboratory contained 10% labeled ALN and 90% free ALN. Cells were incubated with AX-ALN or F-ALN (10 K4 , 10 K5 , and 10 K6 M) in the presence or absence of 100 mM DC and 20 mM chlorpromazine (CP), a clathrin-mediated endocytosis inhibitor, or 1 mM methyl-b-cyclodextrin (MB), a caveolin-mediated endocytosis inhibitor (Thompson et al 2006, Kelley et al 2009, Masaike et al 2010. Western blot analysis Cells (10 5 ) were plated in sixwell plates and cultured in F-12 medium containing 5% FCS.…”

Section: Procedures Of Immunohistochemistry Formentioning

confidence: 99%

Alendronate promotes bone formation by inhibiting protein prenylation in osteoblasts in rat tooth replantation model

Komatsu¹,

Shimada²,

Shibata³

et al. 2013

Journal of Endocrinology

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Bisphosphonates (BPs) are a major class of antiresorptive drug, and their molecular mechanisms of antiresorptive action have been extensively studied. Recent studies have suggested that BPs target bone-forming cells as well as bone-resorbing cells. We previously demonstrated that local application of a nitrogen-containing BP (N-BP), alendronate (ALN), for a short period of time increased bone tissue in a rat tooth replantation model. Here, we investigated cellular mechanisms of bone formation by ALN. Bone histomorphometry confirmed that bone formation was increased by local application of ALN. ALN increased proliferation of bone-forming cells residing on the bone surface, whereas it suppressed the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in vivo. Moreover, ALN treatment induced more alkaline phosphatase-positive and osteocalcin-positive cells on the bone surface than PBS treatment. In vitro studies revealed that pulse treatment with ALN promoted osteocalcin expression. To track the target cells of N-BPs, we applied fluorescencelabeled ALN (F-ALN) in vivo and in vitro. F-ALN was taken into bone-forming cells both in vivo and in vitro. This intracellular uptake was inhibited by endocytosis inhibitors. Furthermore, the endocytosis inhibitor dansylcadaverine (DC) suppressed ALN-stimulated osteoblastic differentiation in vitro and it suppressed the increase in alkaline phosphatase-positive bone-forming cells and subsequent bone formation in vivo. DC also blocked the inhibition of Rap1A prenylation by ALN in the osteoblastic cells. These data suggest that local application of ALN promotes bone formation by stimulating proliferation and differentiation of bone-forming cells as well as inhibiting osteoclast function. These effects may occur through endocytic incorporation of ALN and subsequent inhibition of protein prenylation.

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Identification of Dynamin-2-Mediated Endocytosis as a New Target of Osteoporosis Drugs, Bisphosphonates

Cited by 23 publications

References 39 publications

Notch3 Pathway Alterations in Ovarian Cancer

Notch3 Pathway Alterations in Ovarian Cancer

Dynamin and PTP-PEST cooperatively regulate Pyk2 dephosphorylation in osteoclasts

Alendronate promotes bone formation by inhibiting protein prenylation in osteoblasts in rat tooth replantation model

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